CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects

Abstract

CHEK2 germline pathogenic variants predispose to breast cancer and possibly to other malignancies, with their spectrum and frequency being variable among populations. Τhe majority of CHEK2-associated breast tumors are hormone receptor positive; however, relevant clinical outcomes are not well defined. Herein, we illustrate the histopathological characteristics and clinical outcomes of 52 Greek breast cancer patients who are CHEK2 carriers. Genetic analysis was performed by Sanger/massively parallel sequencing, followed by MLPA. Subsequent haplotype analysis investigated possible founder effects. Blood relatives were offered cascade testing. CHEK2 variant spectrum was characterized by variability, while influenced by founder effects. The majority of carriers, i.e., 60.8%, were diagnosed with breast cancer before the age of 45. Notably, 91.5% of breast tumors were hormone receptor positive. Hormone therapy and mastectomy at diagnosis seem to have a positive trend on overall survival, after a median follow-up of 9.5 years. Remarkably, 41.9% of patients underwent risk-reducing surgery, one third of which involved salpingo-oophorectomy. Nearly half of families responded to cascade testing. Our data highlight the need for guideline-adherent choices, based on the evidence that CHEK2 carriers are at moderate risk for breast cancer and no risk for ovarian cancer, while underscore the possible role of chemoprevention with tamoxifen.

Uncovering the clinical relevance of unclassified variants in DNA repair genes: a focus on BRCA negative Tunisian cancer families

“…The second variant in CHEK2, c.592+3A>T, was identified in one family with both breast and prostate cancer cases and segregation analysis has confirmed the cosegregation of the variant with the disease. This variant was predicted to lead to exon skipping and a recent RNA analysis in the study of Apostolou et al (2021) has confirmed that it leads to exon 3 skipping. In this same study, it was shown that c.592+3A>T is recurrent and founder mutation in the Greek population rising approximately 35 generations ago (Apostolou et al, 2021).…”

“…This variant was predicted to lead to exon skipping and a recent RNA analysis in the study of Apostolou et al (2021) has confirmed that it leads to exon 3 skipping. In this same study, it was shown that c.592+3A>T is recurrent and founder mutation in the Greek population rising approximately 35 generations ago (Apostolou et al, 2021). These findings along with our results support the pathogenic effect of this variant and highlight the need for variant reclassification for better risk assessment and patients' management.…”

Multi-Gene Mutation Profiling by Targeted Next-Generation Sequencing in Premenopausal Breast Cancer

“…This discrepancy may be due to the fact that the CHEK2 c. 1100delC allele is rarely identified in breast cancer patients of Greek descent [ 47 ]. Pathogenic variants in CHEK2 are associated with an increased risk of estrogen receptor-positive breast cancer, although the risk decreases significantly with age, making these carriers more likely to develop the disease prior to menopause [ 48 , 49 ]. Notably, the I157T low-risk allele that was identified in two of our patients is associated with moderate risk and a more favorable prognosis [ 50 ].…”